WO2018045505A1 - New crystalline form of sacubitril sodium salt - Google Patents

Abstract

Provided are new crystalline forms A, B, C, D, and E of sacubitril sodium salt and a method for preparation thereof, pharmaceutical compositions thereof, and application thereof in preparing drugs for enkephalinase-related diseases.

Description

Shakubite sodium salt new crystal form Technical field

The invention relates to the field of pharmaceutical synthesis, in particular to new crystal forms A, B, C, D and E of shakupitide sodium salt and a preparation method thereof.

Background technique

Sacubitril, chemical name 4-{[(2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl -5-oxopentan-2-yl]amino}-4-oxobutanoic acid, an enkephalinase inhibitor, the structure is as follows

Enkephalinase (NEP) is a metalloproteinase expressed in many tissues in the body and expressed most in the kidney. It can catalyze the degradation of various endogenous peptides, such as NP, bradykinin, substance P, etc. Therefore, NEP inhibition The agent can increase the level of urinary natriuretic peptide (NP). NP plays an important role in body fluid balance. NP has three subtypes, type A (ANP), type B (BNP) and type C (CNP). When the blood vessel volume overload causes an atrial pressure increase, the atrium releases ANP, which is also called atrial natriuretic peptide. Increased left ventricular filling pressure can promote BNP release, and ANP and BNP have the effects of relaxing blood vessels and discharging sodium and diuresis. CNP is mainly expressed in the central nervous system, kidney and vascular endothelial cells, and has an antithrombotic effect. Excessive plasma volume and left ventricular filling pressure can stimulate the release of NP, especially in patients with heart failure. Direct vasodilation of NP reduces ventricular preload, systemic vascular resistance, and arterial pressure, and NP can directly vasodilate by reducing ventricular preload, systemic vascular resistance, and arterial pressure. In addition, NP can also increase the filtration rate of glomeruli and promote sodium and water excretion. NP also reduces the release of renin, lowers plasma angiotensin II levels, and relaxes blood vessels.

Angiotensin II (Ang II) is a potent vasoconstrictor and is the most important active hormone in the renin-angiotensin-aldosterone system (RAAS). It plays a major role in cardiovascular disease and can exert a direct boosting effect. . There are at least two subtypes of AngII receptors, AT1 and AT2. AngII is highly selective for the AT1 receptor and 300 times higher than the AT2 receptor. When AngII binds to the AT1 receptor, it activates the corresponding cellular pathway, which shows the main effects of AngII, such as vasoconstriction, aldosterone secretion, renal tubular sodium, and water reabsorption. AT1 receptor antagonists can inhibit AngII-mediated vasoconstriction, as well as renal tubular sodium and water reabsorption; and inhibit the regulation of RAAS on baroreceptors and inhibit sympathetic excitation. AT1 receptor antagonists have been widely used in the treatment of hypertension.

When sulbac or its salt is administered in combination with an angiotensin IIAT1 receptor antagonist, such as valsartan, it can simultaneously inhibit enkephalinase and angiotensin receptor, ie, simultaneously acting on renin - Angiotensin system and promotes brain natriuretic peptides, acting on the neuroendocrine system of the heart in a variety of ways, blocking receptors that exert harmful effects, and promoting protective mechanisms. LCZ-696 (Entresto) developed by Novartis, which is a eutectic composed of sulcoate sodium and valsartan disodium, is used for the treatment of chronic heart failure and/or hypertension, with remarkable effects and good safety. Now the drug has been submitted for new drug listing in the United States, the European Union and other countries, and has been approved by the FDA, becoming the first new drug approved for chronic heart failure in the past 10 years.

Novartis has developed kucurbitate sodium and valsartan disodium into eutectic LCZ-696. One of the reasons is that LCZ-696 is less hygroscopic than sacurbita sodium, which is more conducive to production and storage. Although the LCZ-696 eutectic has improved in physical properties, it has a fixed composition ratio, which limits the ratio of sulbactam to different ratios of valsartan or its pharmaceutically acceptable salt, or other AT1 receptor antagonists. Combination medication is not conducive to clinical adjustment according to different conditions. Shakubite free acid is not suitable for use in preparations, especially oral solid preparations, because of its low melting point and poor water solubility. The amorphous form of the sulphate sodium salt is highly hygroscopic and difficult to prepare. U.S. Patent 5,217,996 discloses a solid form of shakupitide sodium salt X, which is prepared according to the method, and is found to have a high hygroscopicity. Therefore, it is necessary to further study the solid form of the sodium salt of Shakubite in order to obtain the Shakubite sodium salt with simple physical preparation and improved physical properties such as hygroscopicity.

It has been confirmed that it is very difficult to form a sulbactam sodium salt having the desired advantageous properties, and in most cases, a sodium salt form which is poor in stability is obtained, and studies have shown that the crystal form of the sacurbitium salt of the present invention is particularly advantageous.

Summary of the invention

It is an object of the present invention to provide crystal forms A, B, C, D and E of the sacuronium sodium salt.

Another object of the present invention is to provide a process for the preparation of crystalline forms A, B, C, D and E of the sulbactam sodium salt.

The crystal form A of the sulphonic sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 6.0±0.2, 7.0±0.2, 11.8±0.2. 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± 0.2 with peaks; preferably at about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± 0.2 There are peaks.

In one embodiment, the shakubic sodium salt crystal form A has an endothermic peak at a temperature close to 168 ° C at a heating rate of 10 ° C / min.

In one embodiment, the shakubic sodium salt crystal form A has an endothermic peak at 166-169 ° C at a heating rate of 10 ° C / min.

In one embodiment, the Shakusone sodium salt crystal form A has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

In one embodiment, at a heating rate of 10 ° C/min, the sulbactam sodium salt crystal form A has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG.

The DSC plot of Shakube's crystal form A shows an endothermic peak at around 166 °C with a 焓 value of 98.31 J/g. Higher endothermic peak temperatures and enthalpy values indicate a high stability of the crystal lattice of the crystal form. It is worth noting that the crystal form is maintained in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours and a water absorption of 1.4%, while the amorphous form under the same conditions has a high degree of water absorption. 12.8%.

The crystalline form B of the sacuronide sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 5.1 ± 0.2, 10.4 ± 0.2, 11.2 ± 0.2 , 19.2 ± 0.2, 19.7 ± 0.2, 21.3 ± 0.2, 21.8 ± 0.2 with peaks; preferably at about 5.1 ± 0.2, 8.6 ± 0.2, 10.4 ± 0.2, 11.2 ± 0.2, 12.1 ± 0.2, 19.2 ± 0.2, 19.7 ± 0.2 There are peaks at 21.3±0.2 and 21.8±0.2.

In one embodiment, the crystalline form B of the sulbactam sodium salt has an endothermic peak at a heating rate of 10 ° C / min at a temperature close to 133 ° C and near 159 ° C.

In one embodiment, the crystalline form B of the sulbactam sodium salt has a differential scanning amount at a heating rate of 10 ° C / min. The heat map has an endothermic peak at 130-134 ° C and 149-160 ° C.

In one embodiment, the shakusone sodium salt crystal form B has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

In one embodiment, at a heating rate of 10 ° C/min, the shakupyr sodium salt crystal form B has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG.

The crystal form C of the sulphonic sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2 with peaks; preferably at about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2, 12.7 ± 0.2, 14.5 ± 0.2, 16.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, There are peaks at 22.0 ± 0.2, 27.2 ± 0.2.

In one embodiment, the sulphate sodium salt crystal form C has a melting point of about 136 ± 5 °C.

In one embodiment, the shakusone sodium salt crystal form C has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

It is worth noting that the crystal form is maintained in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours and a water absorption of 2.4%, while the amorphous form under the same conditions has a high degree of water absorption. 12.8%.

The crystal form D of the sulbactam sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 5.2 ± 0.2, 8.7 ± 0.2, 10.4 ± 0.2, There are peaks at 12.2±0.2, 15.7±0.2.

In one embodiment, the sulphonic sodium salt crystal form D has a melting point of about 117 ± 5 °C.

In one embodiment, the shakusone sodium salt crystal form D has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

The crystal form E of the shakupitide sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 8.2 ± 0.2, 10.4 ± 0.2, 11.0 ± 0.2, There are peaks at 13.9 ± 0.2, 16.7 ± 0.2, and 21.3 ± 0.2.

In one embodiment, the sulphonic sodium salt crystal form E has a melting point of about 130 ± 5 °C.

In one embodiment, the shakusone sodium salt crystal form E has a powder X-ray diffraction spectrum substantially identical to the powder diffraction pattern shown in FIG.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A, B, C, D or E of the sodium salt of the sulcoxate according to the present invention in admixture with a pharmaceutically acceptable carrier. The pharmaceutical composition can be administered to the gastrointestinal tract. For drug or parenteral administration, it may be administered to a patient in the form of a tablet, capsule, solution, suspension or the like.

The crystalline form A, B, C, D or E of the sacuronium sodium salt of the present invention, or a pharmaceutical composition comprising the same, can be used, for example, for the prevention or treatment of a disease or condition associated with enkephalinase.

The main applications include heart failure, high blood pressure, and cardiomyopathy.

Those skilled in the art are well able to select relevant standard animal experimental models to demonstrate the therapeutic indications and benefits indicated by the context.

In the present invention, "the same powder X-ray diffraction spectrum" means that the positions of the peaks represented by degrees 2θ are substantially the same, and the relative intensities of the peak positions are substantially the same. The relative intensity is the ratio of the intensity of the other peaks to the intensity of the strongest peak when the intensity of the peak having the highest intensity among all the diffraction peaks of the powder X-ray diffraction spectrum is 100%. It is to be noted that the 2θ angle in the X-ray powder diffraction spectrum sometimes has a number of measurement errors due to various factors, and the measured value may vary to a degree of usually ±0.3, preferably ±0.2, more preferably ±0.1. . Therefore, in this specification, based on the actual sample The measured 2 theta angle should be understood to include the meaning of these tolerable errors. "Substantially the same as the powder X-ray diffraction pattern shown in Figure 1" in the present invention means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90 in the powder X-ray diffraction spectrum. %, or at least 95%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.

In addition, the absorption peak in differential scanning calorimetry is an inherent physical property of each crystal form of the present invention. However, in actual measurement, in addition to measurement error, impurities may be mixed in an allowable amount. The possibility of a change in the melting point is also undeniable. Therefore, those skilled in the art can fully understand to what extent the measured value of the endothermic peak temperature in the present invention can be varied. For example, the conceivable error is, in some cases, about ±5 ° C, preferably It is about ± 3 ° C, more preferably about ± 2 ° C, and most preferably about ± 1 ° C.

The "melting point" in the present invention means the initial melting temperature at which the crystal form is melted.

Analytical methods used in the present invention:

1) X-ray powder diffraction

Using a Bruker D8 advance diffractometer, a Cu Ka filled tube (40 kV, 40 mA) was used as an X-ray source with a wide-angle goniometer, a 0.6 mm divergence slit, a 2.5° primary Sora slit, and a 2.5° secondary sora at room temperature. Slit, 8mm anti-scatter slit, 0.1mm detector slit and LynxEye detector. In the 2θ continuous scan mode, data acquisition was performed at a scan speed of 2.4°/min, in a range of 3°-40° with a scan step of 0.02°.

2) Differential scanning calorimeter

Data acquisition was accomplished using TA Q200 and Mettler DSC 1+ under N ₂ protection at a flow rate of 50 mL/min, before ramping from room temperature to degradation temperature at 10 °C/min.

3) Thermogravimetric analyzer

Data collection was accomplished using TA Q500 at a flow rate of 50 mL/min under N ₂ protection from 10 ° C/min to room temperature to 30% or less.

DRAWINGS

Figure 1 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form A;

Figure 2 is a differential scanning calorimetry map (DSC chart) of Shakubite sodium salt crystal form A;

Figure 3 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form B;

Figure 4 is a differential scanning calorimetry map (DSC chart) of Shakubite sodium salt crystal form B;

Figure 5 is a thermogravimetric analysis diagram (TGA diagram) of Shakubite sodium salt crystal form B;

Figure 6 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form C;

Figure 7 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form D;

Figure 8 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form E.

detailed description

The above description of the present invention will be further described in detail by the embodiments of the present invention. However, it should be understood that the present invention is limited to the following examples, and all the inventions based on the above-mentioned contents of the present invention belong to the present invention. The scope of the invention.

Comparative Example 1 Preparation of Shakubite Sodium Salt X

The sulbactam sodium salt X was prepared by the method of Example 1 of US 5,217,996, and the resulting sulphonic acid sodium salt X had a melting point of 159-160 °C.

Comparative Example 2 Preparation of Amorphous Sacrificial Sodium Salt

1.0 g of sirloin free acid was suspended in 10 mL of water, aqueous sodium hydroxide solution (97 mg / 1 mL) was added dropwise, and the mixture was stirred at room temperature for 0.5 h, and the solution was lyophilized to give a white powdery solid.

Example 1 Preparation of Shakubite Sodium Salt Crystal Form A

112 mg of sirolimus was dissolved in 2 mL of ethanol, and 0.1 mL of an ethanol solution containing 10.9 mg of sodium hydroxide was added dropwise thereto, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure, and the obtained residue was obtained from ethanol/n-heptane (1/19, The volume ratio) 300 mL was suspended and stirred overnight, filtered, and dried under vacuum at 40 ° C to give a solid. The solid was added to 10 mL of isopropanol, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid, i.e., type A shakupitr sodium salt.

The solid form of the Shakubite sodium salt crystal form A was characterized by X-ray powder diffraction and differential scanning calorimetry. The solid state characterization parameters and maps are as described herein.

The melting point of the type A shaku sulphate salt was about 167-168 ° C as measured by a melting point apparatus.

Example 2 Preparation of Shakubite Sodium Salt Form B

112 mg of sirolimus was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of this dry solid was dissolved in 0.6 mL of ethanol, and the small glass bottle in which the solution was placed was sealed with a sealing film, and the holes were poured, placed in a glass bottle containing 5 mL of ethyl acetate, and the cap was screwed. After standing at room temperature for 15 days, the small glass bottle was taken out, and the supernatant was discarded by centrifugation to obtain a white solid, that is, B-type shakupitide sodium salt.

The solid form of the Shakubite sodium salt Form B was characterized by X-ray powder diffraction and differential scanning calorimetry. The solid state characterization parameters and maps are as described herein.

The melting of the B-type shaku-salt sodium salt at around 133-136 ° C was measured by a melting point meter.

Example 3 Preparation of Shakubite Sodium Salt Crystal Form C

112 mg of sirolimus was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of this dry solid was added to 1 mL of isopropanol, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid, that is, a C-type shakupitide sodium salt.

The solid form of the Shakubite sodium salt crystal form C was characterized by X-ray powder diffraction, and its solid state characterization parameters and maps are as described herein.

The melting of the C-type shaku-salt sodium salt at about 136 ± 5 ° C was measured by a melting point meter.

Example 4 Preparation of Shakubite Sodium Salt Form D

112 mg of sirolimus was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of this solid was added to 1 mL of 3-pentanone, and after stirring for 72 hours, the supernatant was discarded by centrifugation, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid, that is, a D-type shakupitide sodium salt.

The solid form of Shakupitsa sodium salt Form D was characterized by X-ray powder diffraction, and its solid state characterization parameters and maps are as described herein.

The melting phenomenon of D-type shaku-salt sodium salt at about 117±5 °C was measured by a melting point meter.

Example 5 Preparation of Shakubite Sodium Salt Crystal Form E

112 mg of sirolimus was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of the dried solid was added to 1 mL of 2-butanone, dissolved, and ethyl acetate was added dropwise until turbidity appeared. The supernatant was centrifuged, and the obtained solid was dried in an oven at 40 ° C to obtain a white solid. , that is, E-type shakupi sodium salt.

The solid form characterization parameters and maps of the Shakubite sodium salt crystal form E were as described herein by X-ray powder diffraction.

The E-type shaku-salt sodium salt melted at 130±5 °C as measured by a melting point apparatus.

Example 6 Determination of the hygroscopicity of the crystal form of each of the Sacurbitium sodium salts in the present invention

test methods:

1. Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm) in the artificial climate chamber (set temperature is 25±1 °C, relative humidity is 43.5±2%). weight (m _1).

2. Take the appropriate amount of the crystal form of the present invention, place it in the above weighing bottle and lay it in the weighing bottle. The thickness of the test sample is generally about 1 mm and weighed (m ₂ ).

3. Open the weighing bottle and place it in constant temperature and humidity (setting temperature is 25±1°C, relative humidity is 43.5±2%).

4. Cover the weighing bottle cap before weighing, weigh (m ₃ ), calculate the percentage of water absorption at each time point, percentage of water absorption = (m _{3 -} m ₂ ) / (m _{2 -} m ₁ ) × 100 %.

result:

Table 1

time	Crystal form	Water absorption, %
1.5h	Amorphous	7.1%
1.5h	Shakubite sodium salt X	8.3%
1.5h	Crystal form A	0.6%
1.5h	Form B	0.5%
1.5h	Crystal form C	1.2%
1.5h	Form D	1.5%
1.5h	Form E	2.4%
3h	Amorphous	12.8%
3h	Shakubite sodium salt X	11.0%

3h	Crystal form A	1.4%
3h	Form B	1.0%
3h	Crystal form C	2.4%
3h	Form D	3.2%
3h	Form E	4.3%

From the hygroscopicity data of Table-1, it can be seen that the crystal form of the present invention has a significantly improved water absorption capacity compared to the amorphous form of the Shakubiqu sodium salt, and the Shakubites sodium salt X disclosed in the literature is suitable for further development.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims (15)

1. A crystal form of Shakubite sodium salt characterized in that the crystal form has the following properties:

   Using Cu-Ka radiation, the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± 0.2.
2. The sulbactam sodium salt crystal form A according to claim 1, wherein the differential scanning calorimetry has an endothermic peak at a temperature close to 168 ° C at a heating rate of 10 ° C / min.
3. The crystalline form A of Sacurbitium sodium salt according to claim 1, wherein the differential scanning calorimetry has an endothermic peak at 166-169 ° C under the condition of a heating rate of 10 ° C /min. .
4. A sulbactam sodium salt crystal form B, characterized in that the crystal form has the following properties:

   It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ has peaks at about 5.1±0.2, 10.4±0.2, 11.2±0.2, 19.2±0.2, 19.7±0.2, 21.3±0.2, 21.8±0.2. .
5. The sulbactam sodium salt crystal form B according to claim 4, wherein the differential scanning calorimetry chart is at a temperature close to 133 ° C and close to 159 ° C at a heating rate of 10 ° C / min. Endothermic peak.
6. The crystalline form B of Sacurbitium sodium salt according to claim 4, wherein the differential scanning calorimetry is at 130-134 ° C and 149-160 ° C under a heating rate of 10 ° C / min. There is an endothermic peak.
7. A crystal form of Shakubite sodium salt, characterized in that the crystal form has the following properties:

   It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2.
8. The crystalline form C of the Sacurbitium sodium salt of claim 7 having a melting point of about 136 ± 5 °C.
9. A crystal form of Shakubite sodium salt, characterized in that the crystal form has the following properties:

   Using Cu-Ka radiation, the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at about 5.2 ± 0.2, 8.7 ± 0.2, 10.4 ± 0.2, 12.2 ± 0.2, 15.7 ± 0.2.
10. The crystalline form D of the Sacurbitium sodium salt of claim 9 having a melting point of about 117 ± 5 °C.
11. A crystal form of Shakubite sodium salt characterized in that the crystal form has the following properties:

    Using Cu-Ka radiation, the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at about 8.2 ± 0.2, 10.4 ± 0.2, 11.0 ± 0.2, 13.9 ± 0.2, 16.7 ± 0.2, 21.3 ± 0.2.
12. The crystalline form E of the sulbactam sodium salt of claim 11 having a melting point of about 130 ± 5 °C.
13. A pharmaceutical composition comprising the crystalline form of the Sacurbitium sodium salt according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
14. The use of the Shakubiqu crystal form according to any one of claims 1 to 12 for the preparation of a medicament for treating a disease associated with enkephalinase.
15. The use according to claim 14, wherein the disease comprises heart failure, hypertension and cardiomyopathy.

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